In healthy individuals, the activities of neurons in the subthalamic nucleus (STN), the external globus pallidus (GPe) and basal ganglia output nuclei are poorly correlated, arrhythmic and related to normal movement in a complex manner. In Parkinson's disease (PD) emergent, correlated, rhythmic burst activity in STN, GPe and basal ganglia output neurons is associated with the debilitating symptoms of akinesia, tremor, bradykinesia and rigidity. Reciprocally connected glutamatergic STN and GABAergic GPe neurons that innervate common basal ganglia output neurons are believed to be key mediators of pathological activity. Dopamine depletion in PD may enhance the tendency of the STN-GPe network to support intrinsic oscillatory activity and/or become entrained to low-frequency cortical rhythms via the direct cortical-STN connection. Treatments that correct/ interrupt the pathological activity pattern, such as administration of dopamine precursors/dopamine receptor agonists or high-frequency electrical stimulation of the STN, profoundly ameliorate the symptoms of PD. Deeper understanding of the factors that control the activity pattern of STN and GPe neurons may therefore reveal novel and more effective strategies for the correction/interruption of pathological activity. The central hypothesis of Project 2 is that the abnormal patterning of the STN by cortical and GPe inputs in PD is due (in part) to a reduction in the direct dopaminergic modulation of STN neurons and pathological, adaptive alterations in the intrinsic membrane properties of STN neurons. We will therefore determine how intrinsic membrane properties and synaptic inputs interact to pattern the activity of STN neurons in uirro and in vivo, in normal and dopamine-depleted rodents and non-human primates. Using a combination of electrophysiological, pharmacological, molecular and optical approaches, the laboratories of Drs Bevan, Kita, Osten and Wilson will address 3 Specific Aims: i) determine how voltage- and Ca2+-dependent membrane properties of STN neurons influence the patterning of STN activity by synaptic input m vitro;2) determine how dopamine and dopamine depletion modulate the intrinsic membrane properties of STN neurons and the patterning of STN activity by synaptic input m vitro;3) determine the relative contributions of intrinsic properties and synaptic inputs to the firing pattern of STN neurons in normal and dopamine-depleted animals in vivo. Lay summary: In PD, the STN exhibits a pathological pattern of activity that is associated with motor dysfunction. Correction/interruption of pathological STN activity ameliorates the symptoms of PD. Project 2 will therefore determine the principles underlying pathological STN activity so that more effective therapies for the treatment of PD can be developed.